The abuse of the potent psychostimulant methamphetamine (meth) continues to pose a significant threat not just in the US but also globally. A significant attribute associated with chronic meth induced brain dysfunction is inflammation includes activation of glial cells such as astrocytes and microglia that play a crucial role in modulating inflammation including glutamate excitotoxicity at the synapse. Mounting evidence suggests that inflammation and alterations in glutamate neurotransmission are two novel pathways associated with the pathophysiology in mood disorders. Notably, this cross talk between neurons and glial cells is mediated by extracellular vesicles (EVs) which are emerging as key players in regulating brain function. Chronic meth dependent individuals, including those abstinent and then relapse, display significant behavioral (mood) alterations such as psychosis. A significant gap in knowledge is understanding how meth-induced inflammation perturbs glutamatergic physiology which subsequently impair EV dynamics and exacerbates relapse. Adding another layer of importance is emerging studies showing a role for sex differences with females progressing more quickly to regular use of meth as well as greater dependence and higher relapse rates. Given the lack of studies elucidating the role of EVs with meth relapse between the sexes, our proposed studies are well poised to address this important knowledge gap. Accordingly, the overarching goal of this proposal is to examine the role of EVs in the damaging effects of meth between the sexes using drug-triggered reinstatement (relapse) of extinguished intravenous meth self-administration in rats. Based on our recent preliminary studies with females showing higher inflammation, enhanced glutamatergic alterations, and significantly higher drug-triggered reinstatement (i.e., meth seeking), we hypothesize that EV biogenesis, release, and associated cargo are more impacted in females than males. Using an array of complementing behavioral, molecular, and biochemical approaches in a ?gold standard? preclinical model or reinstatement we will : determine how the anti-inflammatory drug ibudilast alters dynamics of EV release, biogenesis, and associated cargo between the sexes (Aim1); Characterize role of EVs isolated from the sexes on synaptodendritic damage (Aim 2 and) test meth induced changes in EV-associated surface proteins between the sexes (Aim 3). These studies will break new ground and importantly provide novel proof of concept studies which will further serve as a prelude to future basic research on developing EVs as sex-specific medication development for treating meth addiction. .!